APOE ε4/ε4 diminishes neurotrophic function of human iPSC-derived astrocytes
Open accessAbstract
The ε4 allele of the APOE gene encoding apolipoprotein E (apoE) is a strong genetic risk factor for aging-related cognitive decline as well as late-onset Alzheimer's disease (AD) compared to the common ε3 allele. In the central nervous system, apoE is produced primarily by astrocytes and functions in transporting lipids including cholesterol to support neuronal homeostasis and synaptic integrity. Although mouse models and corresponding primary cells have provided valuable tools for studying apoE isoform-dependent functions, recent studies have shown that human astrocytes have a distinct gene expression profile compare with rodent astrocytes. Human induced pluripotent stem cells (iPSCs) derived from individuals carrying specific gene variants or mutations provide an alternative cellular model more relevant to humans upon differentiation into specific cell types. Thus, we reprogramed human skin fibroblasts from cognitively normal individuals carrying APOE ε3/ε3 or ε4/ε4 genotype to iPSC clones and further differentiated them into neural progenitor cells and then astrocytes. We found that human iPSC-derived astrocytes secreted abundant apoE with apoE4 lipoprotein particles less lipidated compared to apoE3 particles. More importantly, human iPSC-derived astrocytes were capable of promoting neuronal survival and synaptogenesis when co-cultured with iPSC-derived neurons with APOE ε4/ε4 astrocytes less effective in supporting these neurotrophic functions than those with APOE ε3/ε3 g…
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APOE has been shown to directly regulate neurite outgrowth in an isoform-dependent manner, with APOE4 inhibiting neurite extension in multiple systems.
“APOE has been shown to directly regulate neurite outgrowth in an isoform-dependent manner, with APOE4 inhibiting neurite extension in multiple systems (Hussain et al., 2013; Nathan et al., 2002; Zhao et al., 2017).”
From APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells (2026) · cites this paper as Zhao et al., 2017
ApoE4 diminishes neurotrophic function of human iPSC-derived astrocytes.
“and diminishes neurotrophic function of human iPSC-derived astrocytes [51].”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [51]
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- Authors
- Zhao, J., Davis, M. D., Martens, Y. A., Shinohara, M., Graff-Radford, N. R., Younkin, S. G., Wszolek, Z. K., Kanekiyo, T., & Bu, G.
- Affiliations
- Department of Neuroscience
- Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA
- Corresponding author
- Bu, Guojun
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-04-21
- Volume
- 26
- Issue
- 14
- Pages
- 2690-2700
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC5886091
- OpenAlex
- W2607261398
- Cited by
- 221
- References
- 10
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 19 · 2023: 32 · 2022: 39 · 2021: 31 · 2020: 31 · 2019: 22 · 2018: 8 · 2017: 3
- FWCI
- 12.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- NIH (RF1AG051504, P50AG016574, R01AG027924, R01AG035355, R01AG046205, and P01 NS074969, R21AG052423)
- NINDS (P50 NS072187, 1U01AG045390-01A1)
- NIA
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- apolipoprotein E, astrocytes, iPSC-derived astrocytes, neurotrophic support, neuronal survival, synaptogenesis, APOE isoforms, Alzheimer's disease, APOE genotype, co-culture, lipoprotein particles, lipid modification
- MeSH terms
- Alleles, Astrocytes, Cells, Cultured, Genotype, Humans, Neurons, Coculture Techniques, Apolipoprotein E3, Apolipoprotein E4, Induced Pluripotent Stem Cells
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